Human epidermal growth factor receptor 2 (HER2/neu) is an oncogenic driver and a proven target for treatment of breast and gastric cancers. The role of HER2/neu and its blockage in various tumors, particularly colorectal adenocarcinoma has been widely explored following the revolutionary impact of anti-HER2/neu therapy in breast and gastric carcinoma patients. This review aimed to highlight the most recent updates on the significance of HER2/neu as a prognostic and predictive factor in these tumors together with its subsequent possible therapeutic indications from preclinical tests and ongoing assessments testing anti-HER2/neu agents in colorectal carcinoma (CRC). In the near future with a growingly tailored therapeutic approach toward cancers, HER2/neu targeted therapeutic strategies may blend into CRC treatment methods.